tbuckley/cabot-search huggingface dataset:
Assessment of Screening for Adverse Childhood Experiences and Receipt of Behavioral Health Services Among Children and Adolescents
Authors: Sonya Negriff, Mercie J. DiGangi, Margo Sidell, Jialuo Liu, Karen J. Coleman
Journal: JAMA Network Open (2022)

Screening for adverse childhood experiences (ACEs) in primary care settings has been increasing as a response to the overwhelming and consistent evidence of the deleterious associations between ACEs and later physical and mental health. However, there is little empirical guidance on the appropriate implementation of ACEs screening in pediatric primary care.To test the use of a pilot intervention for ACEs screening and referral on the receipt of behavioral health care for children and adolescents within a large integrated health care delivery system.A retrospective cohort study was conducted in a large integrated health care system serving Southern California. Child and adolescent members of the target health care system younger than 18 years between July 1, 2018, and November 30, 2021, who received a positive screening for ACEs at the pilot clinic were included. This pilot clinic implemented an intervention that included additional screening questions and incorporated social workers into the process of evaluation and referral for behavioral health needs following ACEs screening.ACEs screening.Visit to a behavioral health care service within 90 days of a positive ACEs screen determined as a score of 1 or higher and behavioral symptoms.The cohort consisted of 4030 children (mean [SD] age, 9.94 [4.55] years) with positive ACEs screening, 48% adolescents (11-17.99 years), approximately equal gender (51% females), 73% Hispanic, and 33% with Medicaid insurance. After the intervention, children were more likely to have a behavioral health services visit within 90 days of the screening than before the intervention (from 4.33% to 32.48%; incidence rate ratio, 7.50; 95% CI, 1.55-36.2).In this cohort study, the implementation of a new ACEs screening and referral process was associated with increased receipt of behavioral health services among children with a positive ACEs screening. This could be useful strategy for other health care systems responding to state and local mandates to screen and provide care for children with ACEs.
A spatially resolved atlas of the human lung characterizes a gland-associated immune niche
Authors: Elo Madissoon, Amanda J. Oliver, Vitalii Kleshchevnikov, Anna Wilbrey-Clark, Krzysztof Polanski, Nathan Richoz, Ana Ribeiro Orsi, Lira Mamanova, Liam Bolt, Rasa Elmentaite, J. Patrick Pett, Ni Huang, Chuan Xu, Peng He, Monika Dabrowska, Sophie Pritchard, Liz Tuck, Elena Prigmore, Shani Perera, Andrew Knights, Agnes Oszlanczi, Adam Hunter, Sara F. Vieira, Minal Patel, Rik G. H. Lindeboom, Lia S. Campos, Kazuhiko Matsuo, Takashi Nakayama, Masahiro Yoshida, Kaylee B. Worlock, Marko Z. Nikolić, Nikitas Georgakopoulos, Krishnaa T. Mahbubani, Kourosh Saeb-Parsy, Omer Ali Bayraktar, Menna R. Clatworthy, Oliver Stegle, Natsuhiko Kumasaka, Sarah A. Teichmann, Kerstin B. Meyer
Journal: Nature Genetics (2022)

Abstract Single-cell transcriptomics has allowed unprecedented resolution of cell types/states in the human lung, but their spatial context is less well defined. To (re)define tissue architecture of lung and airways, we profiled five proximal-to-distal locations of healthy human lungs in depth using multi-omic single cell/nuclei and spatial transcriptomics (queryable at lungcellatlas.org ). Using computational data integration and analysis, we extend beyond the suspension cell paradigm and discover macro and micro-anatomical tissue compartments including previously unannotated cell types in the epithelial, vascular, stromal and nerve bundle micro-environments. We identify and implicate peribronchial fibroblasts in lung disease. Importantly, we discover and validate a survival niche for IgA plasma cells in the airway submucosal glands (SMG). We show that gland epithelial cells recruit B cells and IgA plasma cells, and promote longevity and antibody secretion locally through expression of CCL28, APRIL and IL-6. This new ‘gland-associated immune niche’ has implications for respiratory health.
Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated <i>KRAS</i> G12C
Authors: Rona Yaeger, Jared Weiss, Meredith S. Pelster, Alexander I. Spira, Minal Barve, Sai-Hong I. Ou, Ticiana A. Leal, Tanios S. Bekaii-Saab, Cloud P. Paweletz, Grace A. Heavey, James G. Christensen, Karen Velastegui, Thian Kheoh, Hirak Der-Torossian, Samuel J. Klempner
Journal: New England Journal of Medicine (2022)

Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy.In this phase 1-2, open-label, nonrandomized clinical trial, we assigned heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C to receive adagrasib monotherapy (600 mg orally twice daily) or adagrasib (at the same dose) in combination with intravenous cetuximab once a week (with an initial loading dose of 400 mg per square meter of body-surface area, followed by a dose of 250 mg per square meter) or every 2 weeks (with a dose of 500 mg per square meter). The primary end points were objective response (complete or partial response) and safety.As of June 16, 2022, a total of 44 patients had received adagrasib, and 32 had received combination therapy with adagrasib and cetuximab, with a median follow-up of 20.1 months and 17.5 months, respectively. In the monotherapy group (43 evaluable patients), a response was reported in 19% of the patients (95% confidence interval [CI], 8 to 33). The median response duration was 4.3 months (95% CI, 2.3 to 8.3), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.3). In the combination-therapy group (28 evaluable patients), the response was 46% (95% CI, 28 to 66). The median response duration was 7.6 months (95% CI, 5.7 to not estimable), and the median progression-free survival was 6.9 months (95% CI, 5.4 to 8.1). The percentage of grade 3 or 4 treatment-related adverse events was 34% in the monotherapy group and 16% in the combination-therapy group. No grade 5 adverse events were observed.Adagrasib had antitumor activity in heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C, both as oral monotherapy and in combination with cetuximab. The median response duration was more than 6 months in the combination-therapy group. Reversible adverse events were common in the two groups. (Funded by Mirati Therapeutics; KRYSTAL-1 ClinicalTrials.gov number, NCT03785249.).
Assessment of Depression and Adherence to Guideline-Directed Medical Therapies Following Percutaneous Coronary Intervention
Authors: Matthew E. Lapa, Gretchen M. Swabe, Bruce L. Rollman, Matthew F. Muldoon, Rebecca C. Thurston, Jared W. Magnani
Journal: JAMA Network Open (2022)

Importance Depression is associated with increased risk of primary and secondary cardiovascular events. Medication adherence may play an essential role. Objective To evaluate the association of depression and 12-month adherence to guideline-directed medical therapies (eg, antiplatelet agents, β-blockers, renin-angiotensin-aldosterone system inhibitors [ie, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers], and statins) following percutaneous coronary intervention. Design, Setting, and Participants This retrospective cohort study included individuals who underwent percutaneous coronary intervention from January 1, 2014, to December 31, 2019. Data were collected from a large US health claims database and analyzed between February and August 2022. Main Outcomes and Measures Proportion of days covered (PDC) for classes of guideline-directed medical therapies, with 12-month adherence categorized as adequate (PDC ≥80% to &amp;amp;lt;90%) or optimal (PDC ≥90%). Multivariable-adjusted regression models were used to evaluate the association of depression with adherence; models incorporated demographic characteristics, comorbid medical and psychiatric conditions, depression treatment, and guideline-directed medical therapy treatment adjustment. The hypothesis was that those with depression would have lower odds of either adequate or optimal adherence to agents essential for guideline-directed medical therapy. Results Of 124 443 individuals (mean [SD] age, 69.3 [10.6] years; 41 430 [33.3%] female sex; 3694 [3.0%] Asian, 12 611 [10.1%] Black, and 12 337 [9.9%] Hispanic individuals) who received percutaneous coronary interventions, 20 711 (16.6%) had a diagnosis of depression. Those with depression were significantly less likely to obtain adequate 12-month adherence to antiplatelets (odds ratio [OR], 0.80; 95% CI, 0.77-0.85), β-blockers (OR, 0.84; 95% CI, 0.80-0.88), and statins (OR, 0.88; 95% CI, 0.85-0.93) than those without depression; there was no association between depression and adherence to renin-angiotensin-aldosterone system inhibitors (OR, 0.93; 95% CI, 0.85-1.00). Those with depression had similarly decreased likelihood of optimal 12-month adherence to antiplatelets, β-blockers, and statins as well as renin-angiotensin-aldosterone system inhibitors (OR, 0.87; 95% CI, 0.82-0.94). Conclusions and Relevance In this cohort study, patients with depression were less likely to achieve adequate or optimal adherence to medications essential to guideline-directed medical therapies following percutaneous coronary intervention compared with those without depression. Recognition of depression may facilitate targeted interventions to address medication adherence and thereby improve secondary cardiovascular disease prevention.
Targeting the Progesterone Receptor in Breast Cancer: Mind the Short Form!
Authors: Carlos Ronchi, Cathrin Brisken
Journal: Clinical Cancer Research (2022)

Summary The presurgical window of opportunity trial (WOT) MIPRA provides evidence that neoadjuvant treatment with the progesterone receptor (PR) antagonist mifepristone (RU486) may benefit patients with estrogen receptor–positive (ER+) breast cancer characterized by a high ratio of PR-A versus PR-B isoform (&amp;gt;1.5), suggesting that PR may be targeted in a subset of patients. See related article by Elía et al., p. 866
Circulating Tumor DNA Profiling for Detection, Risk Stratification, and Classification of Brain Lymphomas
Authors: Jurik A. Mutter, Stefan K. Alig, Mohammad S. Esfahani, Eliza M. Lauer, Jan Mitschke, David M. Kurtz, Julia Kühn, Sabine Bleul, Mari Olsen, Chih Long Liu, Michael C. Jin, Charles W. Macaulay, Nicolas Neidert, Timo Volk, Michel Eisenblaetter, Sebastian Rauer, Dieter H. Heiland, Jürgen Finke, Justus Duyster, Julius Wehrle, Marco Prinz, Gerald Illerhaus, Peter C. Reinacher, Elisabeth Schorb, Maximilian Diehn, Ash A. Alizadeh, Florian Scherer
Journal: Journal of Clinical Oncology (2022)

PURPOSE Clinical outcomes of patients with CNS lymphomas (CNSLs) are remarkably heterogeneous, yet identification of patients at high risk for treatment failure is challenging. Furthermore, CNSL diagnosis often remains unconfirmed because of contraindications for invasive stereotactic biopsies. Therefore, improved biomarkers are needed to better stratify patients into risk groups, predict treatment response, and noninvasively identify CNSL. PATIENTS AND METHODS We explored the value of circulating tumor DNA (ctDNA) for early outcome prediction, measurable residual disease monitoring, and surgery-free CNSL identification by applying ultrasensitive targeted next-generation sequencing to a total of 306 tumor, plasma, and CSF specimens from 136 patients with brain cancers, including 92 patients with CNSL. RESULTS Before therapy, ctDNA was detectable in 78% of plasma and 100% of CSF samples. Patients with positive ctDNA in pretreatment plasma had significantly shorter progression-free survival (PFS, P &lt; .0001, log-rank test) and overall survival (OS, P = .0001, log-rank test). In multivariate analyses including established clinical and radiographic risk factors, pretreatment plasma ctDNA concentrations were independently prognostic of clinical outcomes (PFS HR, 1.4; 95% CI, 1.0 to 1.9; P = .03; OS HR, 1.6; 95% CI, 1.1 to 2.2; P = .006). Moreover, measurable residual disease detection by plasma ctDNA monitoring during treatment identified patients with particularly poor prognosis following curative-intent immunochemotherapy (PFS, P = .0002; OS, P = .004, log-rank test). Finally, we developed a proof-of-principle machine learning approach for biopsy-free CNSL identification from ctDNA, showing sensitivities of 59% (CSF) and 25% (plasma) with high positive predictive value. CONCLUSION We demonstrate robust and ultrasensitive detection of ctDNA at various disease milestones in CNSL. Our findings highlight the role of ctDNA as a noninvasive biomarker and its potential value for personalized risk stratification and treatment guidance in patients with CNSL. [Media: see text]
Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study
Authors: Jeremy S. Abramson, Scott R. Solomon, Jon Arnason, Patrick B. Johnston, Bertram Glass, Veronika Bachanova, Sami Ibrahimi, Stephan Mielke, Pim Mutsaers, Francisco Hernandez-Ilizaliturri, Koji Izutsu, Franck Morschhauser, Matthew Lunning, Alessandro Crotta, Sandrine Montheard, Alessandro Previtali, Ken Ogasawara, Manali Kamdar
Journal: Blood (2022)

This global phase 3 study compared lisocabtagene maraleucel (liso-cel) with a standard of care (SOC) as second-line therapy for primary refractory or early relapsed (≤12 months) large B-cell lymphoma (LBCL). Adults eligible for autologous stem cell transplantation (ASCT; N = 184) were randomly assigned in a 1:1 ratio to liso-cel (100 × 106 chimeric antigen receptor-positive T cells) or SOC (3 cycles of platinum-based immunochemotherapy followed by high-dose chemotherapy and ASCT in responders). The primary end point was event-free survival (EFS). In this primary analysis with a 17.5-month median follow-up, median EFS was not reached (NR) for liso-cel vs 2.4 months for SOC. Complete response (CR) rate was 74% for liso-cel vs 43% for SOC (P < .0001) and median progression-free survival (PFS) was NR for liso-cel vs 6.2 months for SOC (hazard ratio [HR] = 0.400; P < .0001). Median overall survival (OS) was NR for liso-cel vs 29.9 months for SOC (HR = 0.724; P = .0987). When adjusted for crossover from SOC to liso-cel, 18-month OS rates were 73% for liso-cel and 54% for SOC (HR = 0.415). Grade 3 cytokine release syndrome and neurological events occurred in 1% and 4% of patients in the liso-cel arm, respectively (no grade 4 or 5 events). These data show significant improvements in EFS, CR rate, and PFS for liso-cel compared with SOC and support liso-cel as a preferred second-line treatment compared with SOC in patients with primary refractory or early relapsed LBCL. This trial was registered at www.clinicaltrials.gov as #NCT03575351.
Effect of Oral β-Glucan on Antibody Response to Ganglioside Vaccine in Patients With High-Risk Neuroblastoma
Authors: Irene Y. Cheung, Audrey Mauguen, Shakeel Modak, Govind Ragupathi, Ellen M. Basu, Stephen S. Roberts, Brian H. Kushner, Nai-Kong Cheung
Journal: JAMA Oncology (2022)

Importance Among patients with high-risk relapsed metastatic neuroblastoma, oral β-glucan adjuvant during GD2/GD3 ganglioside vaccine boost has stimulated IgG antibody response, which was associated with improved survival; however, the effectiveness of oral β-glucan during the vaccine priming phase remains unproven. Objective To isolate the adjuvant effect of oral β-glucan on antibody response to GD2/GD3 ganglioside vaccine in patients with high-risk neuroblastoma. Design, Setting, and Participants In this phase 2 randomized clinical trial, enrolled patients with high-risk neuroblastoma were randomized to 2 groups to receive the GD2/GD3 vaccine at a large cancer center in a major metropolitan area from October 2018 to September 2020. Data were analyzed from October 7, 2021, to February 28, 2022. Interventions Eligible patients receiving GD2/GD3 vaccine were randomly assigned to group 1 (n = 54) to receive no β-glucan or group 2 (n = 53) to receive an oral β-glucan regimen during the first 5 weeks of vaccine priming. From week 6 onwards, all 107 patients received oral β-glucan during vaccine boost for 1 year or until disease progression. Main Outcomes and Measures Primary end point was comparison of anti-GD2 IgG1 response before vaccine injection 6 (week 32) in group 1 vs group 2. Seroconversion rate and the association of antibody titer with β-glucan receptor dectin-1 single nucleotide polymorphism (SNP) rs3901533 were also assessed. Results In all, 107 patients with high-risk neuroblastoma were randomized to the 2 groups: 54 patients (median [range] age, 5.2 [1.0-17.3] years; 28 [52%] male and 26 [48%] female) in group 1; and 53 patients (median [range] age, 6.2 [1.9-18.4] years; 25 [47%] male and 28 [53%] female) in group 2; both groups were also comparable in their first remission status at study entry (70% vs 70%). Adding oral β-glucan during the first 5 weeks of vaccine priming elicited a higher anti-GD2 IgG1 antibody response in group 2 (1.80; 90% CI, 0.12-3.39; P = .08; planned type I error, 0.10). Anti-GD2 IgG1 titer of 230 ng/mL or greater by week 8 was associated with statistically favorable PFS. Antibody titer correlated significantly with dectin-1 SNP. The genotype frequency, seroconversion rates, and vaccine-related toxic effects were similar in the 2 groups. Conclusions and Relevance This phase 2 randomized clinical trial found that adding oral β-glucan during vaccine priming increased anti-GD2 IgG1 titer among genetic responders without added toxic effects. Because responder dectin-1 SNP was identical in the 2 randomized groups, no difference was detected in seroconversion rates. Alternative or additional adjuvants may be needed to enhance seroconversion. Trial Registration ClinicalTrials.gov Identifier: NCT00911560
Stromal Reprogramming through Dual PDGFRα/β Blockade Boosts the Efficacy of Anti–PD-1 Immunotherapy in Fibrotic Tumors
Authors: Takahiko Akiyama, Tadahito Yasuda, Tomoyuki Uchihara, Noriko Yasuda-Yoshihara, Benjy J.Y. Tan, Atsuko Yonemura, Takashi Semba, Juntaro Yamasaki, Yoshihiro Komohara, Koji Ohnishi, Feng Wei, Lingfeng Fu, Jun Zhang, Fumimasa Kitamura, Kohei Yamashita, Kojiro Eto, Shiro Iwagami, Hirotake Tsukamoto, Terumasa Umemoto, Mari Masuda, Osamu Nagano, Yorifumi Satou, Hideyuki Saya, Patrick Tan, Hideo Baba, Takatsugu Ishimoto
Journal: Cancer Research (2022)

Abstract Excess stroma and cancer-associated fibroblasts (CAF) enhance cancer progression and facilitate immune evasion. Insights into the mechanisms by which the stroma manipulates the immune microenvironment could help improve cancer treatment. Here, we aimed to elucidate potential approaches for stromal reprogramming and improved cancer immunotherapy. Platelet-derived growth factor C (PDGFC) and D expression were significantly associated with a poor prognosis in patients with gastric cancer, and PDGF receptor beta (PDGFRβ) was predominantly expressed in diffuse-type gastric cancer stroma. CAFs stimulated with PDGFs exhibited markedly increased expression of CXCL1, CXCL3, CXCL5, and CXCL8, which are involved in polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) recruitment. Fibrotic gastric cancer xenograft tumors exhibited increased PMN-MDSC accumulation and decreased lymphocyte infiltration, as well as resistance to anti–PD-1. Single-cell RNA sequencing and spatial transcriptomics revealed that PDGFRα/β blockade reversed the immunosuppressive microenvironment through stromal modification. Finally, combining PDGFRα/β blockade and anti–PD-1 treatment synergistically suppressed the growth of fibrotic tumors. These findings highlight the impact of stromal reprogramming on immune reactivation and the potential for combined immunotherapy for patients with fibrotic cancer. Significance: Stromal targeting with PDGFRα/β dual blockade reverses the immunosuppressive microenvironment and enhances the efficacy of immune checkpoint inhibitors in fibrotic cancer. See related commentary by Tauriello, p. 655
A Literature Review of the Effects of Air Pollution on COVID-19 Health Outcomes Worldwide: Statistical Challenges and Data Visualization
Authors: A. Bhaskar, J. Chandra, H. Hashemi, K. Butler, L. Bennett, Jacqueline Cellini, Danielle Braun, Francesca Dominici
Journal: Annual Review of Public Health (2022)

Several peer-reviewed papers and reviews have examined the relationship between exposure to air pollution and COVID-19 spread and severity. However, many of the existing reviews on this topic do not extensively present the statistical challenges associated with this field, do not provide comprehensive guidelines for future researchers, and review only the results of a relatively small number of papers. We reviewed 139 papers, 127 of which reported a statistically significant positive association between air pollution and adverse COVID-19 health outcomes. Here, we summarize the evidence, describe the statistical challenges, and make recommendations for future research. To summarize the 139 papers with data from geographical locations around the world, we also present anopen-source data visualization tool that summarizes these studies and allows the research community to contribute evidence as new research papers are published.
Analysis of Daily Ambient Temperature and Firearm Violence in 100 US Cities
Authors: Vivian H. Lyons, Emma L. Gause, Keith R. Spangler, Gregory A. Wellenius, Jonathan Jay
Journal: JAMA Network Open (2022)

Importance Firearm violence is a leading public health crisis in the US. Understanding whether and how ambient temperature is associated with firearm violence may identify new avenues for prevention and intervention. Objective To estimate the overall and regional association between hotter temperatures and higher risk of firearm violence in the US. Design, Setting, and Participants This cross-sectional study used distributed lag nonlinear models, controlling for seasonality and long-term time trends by city and pooled results overall and by climate region. The most populous cities in the US with the highest number of assault-related firearm incidence (ie, shootings) from 2015 to 2020 were analyzed. Data analysis was performed from October 2021 to June 2022. Exposures Maximum daily temperature by city. Main Outcomes and Measures The primary outcome was the number of assault-related firearm shootings by city. Results A total of 116 511 shootings in 100 cities were included in this analysis. The pooled analysis estimated that 6.85% (95% CI, 6.09%-7.46%) of all shootings were attributable to days hotter than city-specific median temperatures. This equates to 7973 total shootings (95% CI, 7092-8688 total shootings) across the 100 cities over the 6-year study period, although the number of total persons injured or killed would be higher. Estimated risk of firearm incidents increased almost monotonically with higher temperatures, with a local peak at the 84th percentile of the temperature range corresponding to a relative risk of 1.17 (95% CI, 1.12-1.21) compared with the median temperature. However, even moderately hot temperatures were associated with higher risk of shootings. Although significant, there was low heterogeneity between cities ( I 2 = 11.7%; Cochran Q test, P = .02), indicating regional or climate-specific variation in the daily temperature and incident shootings relationship. Conclusions and Relevance These findings underscore the importance of heat adaptation strategies broadly throughout the year to reduce shootings, rather than focusing on only the hottest days.